The candidate for this NCI Career Development Award is Marco Davila, MD, PhD, who is currently a medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Davila's PhD thesis work identified a role for cryptic recombination signals (cRS) in V(D)J rearrangement during mouse B cell development. Furthermore, the project was related to lymphomagenesis since rearrangement of some cRS are known to be oncogenic in B cells. At MSKCC he has joined the laboratory of Dr. Michel Sadelain, who is a worldwide leader in the field of T cell therapy for cancer. An immediate term goal of the candidate is to complete the aims of this proposal, which are dedicated to investigating T cells genetically modified with chimeric antigen receptors (CARs) to target them to tumors. Furthermore, the completion of these aims will provide the candidate intellectual and technical skills required to become an independent investigator, which is another immediate term goal. The long-term goals of the candidate are to become an academic medical oncologist that develops immunotherapies in mice and applies them to patients. Gene-modified T cell function in humans has been limited to date and we propose this is due to the mouse models used to develop them. The mouse models were immunodeficient so they could not account for the affect of a complete immune system on the function of gene-modified T cells in humans. Therefore, we have developed an immunocompetent mouse model to study the in vivo function of anti-CD19 T cells. We will treat wild type mice with anti-CD19 T cells and measure the duration of B cell aplasia. Furthermore, we will modify signal transduction elements or suppress negative immunoregulatory elements to determine if gene- modified T cell function is enhanced. However, the ultimate requirement of any gene-modified T cell therapy is that it kills cancer. Therefore, we will also treat E<-myc mice, which are pre-disposed to lymphomas due to a myc transgene, with anti-CD19 T cells to determine if there is an improvement in tumor burden and/or survival. The completion of this project will lead to an optimized anti-CD19 T cell therapy in immunocompetent mice. It is also expected that the results will be used to develop a clinical trial for patients with lymphomas. MSKCC is an ideal site for this project because of the intellectual and technical resources available. Core and animal care facilities will facilitate the mouse studies. Also, the large research community supports frequent seminars involving relevant topics such as immunotherapy, cancer biology, immunology, and gene therapy. Furthermore, there is a wealth of physician-scientists and other investigators available to provide feedback and serve as mentors to the candidate. In fact, three highly qualified physician-scientists have agreed to serve on an Advisory Committee to assist the candidate's research and professional development. This Career Development award will support the research project and professional development of Dr. Davila thereby enabling the realization of his immediate goals and assisting him towards his long-term ones. PUBLIC HEALTH RELEVANCE: This research project is significant because it represents the first comprehensive pre- clinical analysis of the impact of the immune system on adoptively transferred, gene-modified T cells. It is expected that the results from this study will be used to develop optimized T cell therapies for patients with lymphoma.